APPLICANT'S ABSTRACT: The overall objective of the proposed study is to define the mechanism by which acute ethanol exposure prior to thermal injury increases morbidity and mortality. Nearly 100,000 people each year are admitted to hospitals due to burn injury and about half of those patients are reported to have been drinking alcohol. Alcohol exposure is not only a risk factor for the events that lead up to the fire related accidents, but that alcohol exposure also leads to increased morbidity and mortality among burned patients. Burn patients who had moderate to high blood alcohol levels on admission stayed in the hospital twice as long, required 60% more surgical procedures and more rigorous antibiotic therapy, and were twice as likely to suffer serious infectious complications than burn patients not exposed to alcohol having the same degree and surface area of body burns. We hypothesize that these complications arise in alcohol exposed individuals because of enhancement of the immunosuppression observed following burn injury which is triggered by ethanol consumption. Herein, we proposed to employ both in vivo and in vitro analyses to determine whether acute ethanol exposure prior to thermal injury 1) enhances immunosuppression and 2) increases the magnitude of pulmonary pathology in mice subjected to thermal injury. Additionally, we plan to define the roles of key proinflammatory and immunomodulatory cytokines produced during the early stages immunosuppression and the development of pulmonary pathology in ethanol-exposed, thermally injured mice, and determine whether modulation of specific mediators (by the addition of exogenous cytokines and/or anticytokine antibodies) can restore immunocompetence and ameliorate the pulmonary pathology. It is anticipated that these studies will provide valuable information which can be used to develop more efficacious therapies for the treatment of ethanol-exposed, thermally-injured patients.